PPAPDC1B and WHSC1L1 are common drivers of the 8p11-12 amplicon, not only in breast tumors but also in pancreatic adenocarcinomas and lung tumors

Am J Pathol. 2013 Nov;183(5):1634-1644. doi: 10.1016/j.ajpath.2013.07.028. Epub 2013 Sep 17.

Abstract

Amplification of the 8p11-12 chromosomal region is a common genetic event in many epithelial cancers. In breast cancer, several genes within this region have been shown to display oncogenic activity. Among these genes, the enzyme-encoding genes, PPAPDC1B and WHSC1L1, have been identified as potential therapeutic targets. We investigated whether PPAPDC1B and WHSC1L1 acted as general driver genes, thereby serving as therapeutic targets in other tumors with 8p11-12 amplification. By using publicly available genomic data from a panel of 883 cell lines derived from different cancers, we identified the cell lines presenting amplification of both WHSC1L1 and PPAPDC1B. In particular, we focused on cell lines derived from lung cancer and pancreatic adenocarcinoma and found a correlation between the amplification of PPAPDC1B and WHSC1L1 with their overexpression. Loss-of-function studies based on the use of siRNA and shRNA demonstrated that PPAPDC1B and WHSC1L1 played a major role in regulating the survival of pancreatic adenocarcinoma and small-cell lung cancer-derived cell lines, both in anchorage-dependent and anchorage-independent conditions, displaying amplification and overexpression of these genes. We also demonstrated that PPAPDC1B and WHSC1L1 regulated xenograft growth in these cell lines. Finally, quantitative RT-PCR experiments after PPAPDC1B and WHSC1L1 knockdown revealed exclusive PPAPDC1B and WHSC1L1 gene targets in small-cell lung cancer and pancreatic adenocarcinoma-derived cell lines compared with breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / pathology
  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival / genetics
  • Chromosomes, Human, Pair 8 / genetics*
  • Female
  • Gene Amplification*
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Histone-Lysine N-Methyltransferase / genetics*
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Nude
  • Nuclear Proteins / genetics*
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology
  • Phosphatidate Phosphatase / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / metabolism
  • Small Cell Lung Carcinoma / genetics
  • Small Cell Lung Carcinoma / pathology
  • Xenograft Model Antitumor Assays

Substances

  • Nuclear Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Histone-Lysine N-Methyltransferase
  • NSD3 protein, human
  • PLPP5 protein, human
  • Phosphatidate Phosphatase

Supplementary concepts

  • Pancreatic Carcinoma